Submissions for variant NM_002485.5(NBN):c.1777C>G (p.Pro593Ala)

gnomAD frequency: 0.00059  dbSNP: rs146989944

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000656929	SCV000149694	uncertain significance	not provided	2023-05-05	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with a personal or family history of breast and/or ovarian cancer (Haiman et al., 2013; Tung et al., 2015); This variant is associated with the following publications: (PMID: 23555315, 25186627)
Ambry Genetics	RCV000115785	SCV000186185	benign	Hereditary cancer-predisposing syndrome	2021-07-13	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000988083	SCV000254769	likely benign	Microcephaly, normal intelligence and immunodeficiency	2025-02-03	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000212750	SCV000595914	uncertain significance	not specified	2016-04-27	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000656929	SCV001134498	likely benign	not provided	2022-12-08	criteria provided, single submitter	clinical testing
Mendelics	RCV000988083	SCV001137660	likely benign	Microcephaly, normal intelligence and immunodeficiency	2019-05-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212750	SCV001360495	likely benign	not specified	2019-01-18	criteria provided, single submitter	clinical testing	Variant summary: NBN c.1777C>G (p.Pro593Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00019 in 276572 control chromosomes, predominantly at a frequency of 0.0022 within the African subpopulation in the gnomAD database. The observed variant frequency within African control individuals in the gnomAD database is approximately 17.6 fold of the estimated maximal expected allele frequency for a pathogenic variant in NBN causing Hereditary Breast and Ovarian Cancer phenotype (0.00013), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. c.1777C>G has been reported in the literature in individuals affected with Breast and Ovarian Cancer (Haiman_2013, Tung_2014). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variant(s) have been reported (BRCA2 c.2808_2811delACAA, p.Ala938fsX21), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, 4 classify as VUS while 1 classified as likley benign. Based on the evidence outlined above, the variant was classified as likely benign.
Genome-Nilou Lab	RCV000988083	SCV002045904	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2021-11-07	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115785	SCV002536619	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-21	criteria provided, single submitter	curation
PreventionGenetics, part of Exact Sciences	RCV003891614	SCV000806419	likely benign	NBN-related disorder	2022-03-17	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).